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At least 739 records · Page 41Linked to original sources
PubMed1987

L-triiodothyronine stimulates growth by means of an autocrine factor in a cultured growth-hormone-producing cell line.

L-Triiodothyronine (T3) stimulates DNA synthesis and replication of cultured GC cells, a T3-responsive growth hormone (GH)-secreting cell line. To determine whether T3 stimulates secretion of an autocrine growth factor, we compared the growth-promoting activity of medium conditioned by T3-stimulated and T3-depleted cells to that of unconditioned medium. Addition of polyclonal rabbit anti-T3 serum to T3-containing media decreased cellular T3 content by 50-70%. In unconditioned medium, anti-T3 serum decreased T3-induced cell growth and GH production by 40-70%. In conditioned medium, anti-T3 serum also effected a 45-70% decrease in induction of GH secretion but did not attenuate the growth-promoting activity. Growth-promoting activity was not detected in medium conditioned by T3-depleted cells. Thus, conditioned medium from T3-containing GC cell cultures contains growth-promoting activity that is independent of T3. Further, the induction of GC cel growth by T3 may occur, at least in part, by induction of an autocrine growth factor.

Cell Division↗
PubMed1988

Interleukin 1 binds to specific receptors on human keratinocytes and induces granulocyte macrophage colony-stimulating factor mRNA and protein. A potential autocrine role for interleukin 1 in epidermis.

Cultured human keratinocytes have been shown to produce IL-1 alpha and beta mRNA and protein. IL-1 biological activity has been identified in normal human epidermis; in vitro, most biologically active IL-1 resides in a cell-associated compartment. The potential for autocrine effects of IL-1 on human keratinocytes was assessed by measurement of keratinocyte IL-1 receptors. Both high- and low-affinity cell surface receptors that bound recombinant (r) IL-1 alpha and beta with comparable affinities could be identified on cultured human keratinocytes, using 125I-labeled rIL-1. Chemical crosslinking experiments identified a cell surface molecule of roughly 72,500 Mr that bound 125I-labeled IL-1, similar to the molecular weight of previously described IL-1 receptors on fibroblasts, B cells, and T cells. To assess the biological consequences of keratinocyte IL-1 binding, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression was measured. The addition of exogenous rIL-1 alpha led to a dose-dependent increase in the accumulation of GM-CSF mRNA, as measured by a sensitive and specific S1 nuclease assay. This increase in mRNA was reflected in a marked increase in GM-CSF biological activity as measured by proliferation of blast cells from chronic myelogenous leukemia patients. The biological activity was completely inhibitable by an antibody to human rGM-CSF. GM-CSF activates mature neutrophils and macrophages and appears to enhance the efficiency of Langerhans cell antigen presentation to T cells. Release of IL-1 from injured or activated keratinocytes may lead to enhanced epidermal GM-CSF gene expression via an autocrine mechanism, thus enhancing local host defense.

Cells, Cultured↗
PubMed1989

Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control.

Autonomous in vitro growth of myeloid leukemic colony-forming cells may in part result from autocrine production of colony-stimulating factors (CSF). Some acute myeloid leukemia (AML) samples, however, fail to synthesize CSF despite growing autonomously in agar, and are therefore believed to bypass CSF requirements. Cytokines such as IL-6, tumor necrosis factor (TNF)-alpha, and IL-1, products of cells of the myeloid lineage, are known to be involved in growth control of myeloid progenitor cells. Since these molecules may also contribute to autocrine and paracrine growth regulation of myeloid leukemias, we screened a series of AML for cytokine production. In addition, possible roles of IL-6, TNF-alpha, and IL-1 in growth control of AML were investigated in vitro. We show that a substantial proportion of AML cells produce IL-6, TNF-alpha, and IL-1-beta and use these mediators to stimulate their growth by disparate mechanisms: IL-6 acts as a costimulator to enhance CSF-induced clonogenicity of AML blasts. TNF-alpha induces CSF production by endothelial cells and may therefore provide a paracrine loop to support leukemia growth.

Colony-Stimulating Factors↗
PubMed1991

Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation of the mouse BC3H-1 muscle cell line. Differentiation from myoblasts to myocytes was associated with a 60% decrease in IGF-I receptor sites determined by Scatchard analysis. Analysis of mRNA abundance and protein labeling studies indicated that the decrease in IGF-I receptor sites was associated with similar reductions in IGF-I receptor gene expression and receptor biosynthesis. IGF-II peptide gene expression was detected in myoblasts and increased 15-fold with differentiation; the increase in IGF-II gene expression preceded the decrease in IGF-I receptor gene expression. In contrast, IGF-I peptide gene expression was low in myoblasts and decreased slightly with differentiation. To explore the potential role of endogenous IGF-II in the differentiation-associated decrease in IGF-I receptor expression, we investigated the effects of IGF-II treatment in myoblasts. The addition of IGF-II to undifferentiated myoblasts resulted in downregulation of the IGF-I receptor which was associated with decreased IGF-I receptor biosynthesis and decreased IGF-I receptor mRNA abundance. These studies suggest, therefore, that IGF-I receptor expression during muscle cell differentiation may be regulated, at least in part, through autocrine production of IGF-II.

Animals↗
PubMed1991

Autocrine stimulation by erythropoietin and autonomous growth of human erythroid leukemic cells in vitro.

Autonomous colony formation is a frequent event in erythroleukemia. In 13 cases of early erythroid leukemias, we investigated whether erythropoietin (Epo) autocrine stimulation was responsible for the growth factor autonomy. Epo transcripts were detected by Northern blotting in cells from one patient. These cells also expressed an Epo receptor (1,000 receptors per cell) with a 420-pM affinity and Epo was detected in the supernatant of cultured cells. In 8 of the 13 cases, Epo transcripts were revealed by the polymerase chain reaction ranging from 0.5 to 500 copies per cell. In situ hybridization proved that these Epo transcripts were present in the blast cells. No Epo gene abnormalities were detected by Southern blotting. In two cases, leukemic cells were grown in the presence of Epo-neutralizing antibodies or Epo antisense oligomers. In one case, the antibody significantly reduced autonomous growth. In contrast, the antibody had no effect in the second case in which blast cells transcribed the Epo gene at a low level. However, Epo antisense oligomers partially inhibited autonomous growth. This inhibition was reversed by addition of exogenous Epo. Overall, these results suggest that an extracellular or intracellular autocrine Epo stimulation occurs in some cases of erythroid malignancies.

Base Sequence↗
PubMed1992

Autocrine angiotensin system regulation of bovine aortic endothelial cell migration and plasminogen activator involves modulation of proto-oncogene pp60c-src expression.

Rapid endothelial cell migration and inhibition of thrombosis are critical for the resolution of denudation injuries to the vessel wall. Inhibition of the endothelial cell autocrine angiotensin system, with either the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin II receptor antagonist sar1, ile8-angiotensin II, leads to increased endothelial cell migration and urokinase-like plasminogen activator (u-PA) activity (Bell, L., and J. A. Madri. 1990. Am. J. Pathol. 137:7-12). Inhibition of the autocrine angiotensin system with the converting-enzyme inhibitor or the receptor antagonist also leads to increased expression of the proto-oncogene c-src: pp60c-src mRNA increased 7-11-fold, c-src protein 3-fold, and c-src kinase activity 2-3-fold. Endothelial cell expression of c-src was constitutively elevated after stable infection with a retroviral vector containing the c-src coding sequence. Constitutively increased c-src kinase activity reconstituted the increases in migration and u-PA observed with angiotensin system interruption. Antisera to bovine u-PA blocked the increase in migration associated with increased c-src expression. These data suggest that increases in endothelial cell migration and plasminogen activator after angiotensin system inhibition are at least partially pp60c-src mediated. Elevated c-src expression with angiotensin system inhibition may act to enhance intimal wound closure and to reduce luminal thrombogenicity in vivo.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1992

Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II.

Recent observations in our laboratory suggest that angiotensin II (Ang II) is a bifunctional vascular smooth muscle cell (VSMC) growth modulator capable of inducing hypertrophy or inhibiting mitogen-stimulated DNA synthesis. Because transforming growth factor-beta 1 (TGF beta 1) has similar bifunctional effects on VSMC growth, we hypothesized that autocrine production of TGF beta 1 may mediate the growth modulatory effects of Ang II. Indeed, this study demonstrates that Ang II induces a severalfold increase in TGF beta 1 mRNA levels within 4 h that is dependent on de novo protein synthesis and appears to be mediated by activation of protein kinase C (PKC). Ang II not only stimulates the synthesis of latent TGF beta 1, but also promotes its conversion to the biologically active form as measured by bioassay. The coincubation of VSMCs with Ang II and control IgG has no significant mitogenic effect. However, the co-administration of Ang II and the anti-TGF beta 1 antibody stimulates significantly DNA synthesis and cell proliferation. We conclude that: (a) Ang II induces increased TGF beta 1 gene expression via a PKC dependent pathway involving de novo protein synthesis; (b) Ang II promotes the conversion of latent TGF beta 1 to its biologically active form; (c) Ang II modulates VSMC growth by activating both proliferative and antiproliferative pathways; and (d) Autocrine active TGF beta 1 appears to be an important determinant of VSMC growth by hypertrophy or hyperplasia.

Angiotensin II↗
PubMed1993

Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II.

Angiotensin (Ang) II stimulates hypertrophic growth of vascular smooth muscle cells (VSMC). Accompanying this growth is the induction of the expression of growth-related protooncogenes (c-fos, c-jun, and c-myc), as well as the synthesis of the autocrine growth factors, such as PDGF-A and TGF-beta 1. In this study, we demonstrate further that Ang II also induces the synthesis of basic fibroblast growth factor (bFGF), a potent mitogen for VSMC. To examine how these factors interact to modulate the growth response of VSMC to Ang II, we used antisense oligomers to determine the relative contribution of these three factors. Treatment of confluent, quiescent smooth muscle cells with specific antisense oligomers complementary to bFGF, PDGF-A, and TGF-beta 1 efficiently inhibited the syntheses of these factors. Our results demonstrate that in these VSMC, TGF-beta 1 affects a key antiproliferative action, modulating the mitogenic properties of bFGF. Autocrine PDGF exerts only a minimal effect on DNA synthesis. An imbalance in these signals activated by Ang II may result in abnormal VSMC growth leading to the development of vascular disease.

3T3 Cells↗
PubMed1994

Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta.

Previous investigations have demonstrated that growing mesangial cells in high glucose concentration stimulates extracellular matrix synthesis and also increases the expression of TGF-beta. We tested whether the stimulation of extracellular matrix production is mediated by autocrine activation of TGF-beta, a known prosclerotic cytokine. Addition of neutralizing anti-TGF-beta antibody, but not normal rabbit IgG, significantly reduced the high glucose-stimulated incorporation of 3[H]proline. Denaturing SDS-PAGE revealed that mainly collagen types I and IV were stimulated by high (450 mg/dl) D-glucose. This high glucose-mediated increase in collagen synthesis was reduced by the anti-TGF-beta antibody. Treatment of mesangial cells grown in normal (100 mg/dl) D-glucose with 2 ng/ml recombinant TGF-beta 1 mimicked the effects of high glucose. Furthermore, the anti-TGF-beta antibody significantly reduced the increase in mRNA levels encoding alpha 2(I) and alpha 1(IV) collagens induced by high glucose. Thus, the high glucose-stimulated increase of collagen production in mesangial cells is mediated, at least in part, by autocrine TGF-beta activation. We postulate that the interception of the glomerular activity of TGF-beta may be an effective intervention in the management of diabetic nephropathy.

Animals↗
PubMed1994

Autocrine and paracrine effects of atrial natriuretic peptide gene transfer on vascular smooth muscle and endothelial cellular growth.

In addition to the atria, recent evidence suggests that atrial natriuretic peptide (ANP) is also synthesized in other tissues. Of particular interest is the location of ANP mRNA in the vessel wall. We and others have shown that exogenously added ANP inhibited the growth of endothelial cells and vascular smooth muscle cells (VSMC) in culture. However, it is not known if the locally synthesized ANP would act similarly. Because cultured endothelial cells and VSMC have lost the ability to express the endogenous ANP gene, we have transfected cells in culture with an expression vector expressing rat ANP and have examined the effects on growth. Cultured endothelial cells transfected with an ANP expression vector synthesized and secreted high levels of ANP. These cells also showed significantly lower rates of DNA synthesis under basal and fibroblast growth factor (FGF)-stimulated conditions. Addition of conditioned medium from endothelial cells transfected with ANP vector to nontransfected endothelial cells resulted in the significant increase in cyclic GMP. Similarly, conditioned media collected from endothelial cells transfected with ANP vector also decreased DNA synthesis in VSMC. Coculture of ANP-transfected endothelial cells with quiescent VSMC showed that released ANP from endothelial cells inhibited DNA synthesis in VSMC. Finally, we examined the autocrine effect of direct transfection of ANP vector into VSMC. Transfection of the ANP vector decreased DNA synthesis in VSMC under basal and angiotensin II-stimulated conditions. Similarly, transfection of the ANP vector resulted in a decrease in the PDGF and serum (5%)-stimulated DNA synthesis of VSMC. These results demonstrate that endogenously produced ANP can exert autocrine and paracrine inhibitory effects on endothelial cell and VSMC growth. In vivo gene transfer of ANP may provide us with the opportunity of gene therapy for vascular diseases in which the abnormalities are vasoconstriction and pathological growth.

Animals↗
PubMed1994

Disruption by interferon-alpha of an autocrine interleukin-6 growth loop in IL-6-dependent U266 myeloma cells by homologous and heterologous down-regulation of the IL-6 receptor alpha- and beta-chains.

IL-6 is an autocrine growth factor for U266 myeloma cells and their growth is inhibited by IFN-alpha or IL-6 mAb. We asked, therefore, whether IFN-alpha-induced growth inhibition involved IL-6. IFN-alpha and mAb against IL-6, the IL-6R alpha-(gp80) or beta-chain (gp130) potently inhibited U266 cells. Remarkably, this effect occurred despite IFN-alpha-augmented secretion of endogenous IL-6. However, examining the IL-6R revealed that IFN-alpha drastically curtailed expression of the IL-6R alpha- and beta-chain. This effect occurred on two different levels (protein and mRNA) and by two different mechanisms (directly and indirectly through IL-6). First, IFN-alpha, but not IL-6, greatly decreased gp80 and, to a lesser extent, gp130 mRNA levels which resulted in a loss of IL-6 binding sites. Second, IFN-alpha-induced IL-6 predominantly down-regulated membrane-bound gp130. IFN-alpha-mediated decrease of gp80 levels was not detected on IL-6-independent myeloma (RPMI 8226) or myeloid cells (U937). We conclude that IFN-alpha inhibited IL-6-dependent myeloma cell growth by depriving U266 cells of an essential component of their autocrine growth loop, a functional IL-6R.

Affinity Labels↗
PubMed1993

Breastfeeding after pituitary resection: support for a theory of autocrine control of milk supply?

A 20-year-old woman with a history of pituitary resection complicated by diabetes insipidus was able to fully breastfeed for three months despite apparent hyposecretion of pituitary hormones. This case report adds to the growing body of evidence that control of milk production shifts from endocrine to autocrine control shortly after delivery. Autocrine control allows efficient regulation of milk supply to match the needs of the infant. A recently discovered factor in human milk that inhibits lactose and casein synthesis in vitro is believed to be responsible for local, short term control of milk production. This study suggests that practices which result in infrequent or incomplete removal of milk from the breast lead to decreased milk production and should be abandoned.

Abscess↗
PubMed2002

Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor.

The expression/function of vascular endothelial growth factor (VEGF) receptors (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is under scrutiny. We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo) lineage. KDR, expressed on 0.5% to 1.5% CD34(+) cells, is rapidly downmodulated on induction of differentiation. Similarly, Flt1 is present at very low levels in HPCs and is downmodulated in E and G lineages; however, Flt1 is induced in the precursors of both Mo and Mk series; ie, its level progressively increases during Mo maturation, and it peaks at the initial-intermediate culture stages in the Mk lineage. Functional experiments indicate that Mk and E, but not G and Mo, precursors release significant amounts of VEGF in the culture medium, particularly at low O(2) levels. The functional role of VEGF release on Mk maturation is indicated by 2 series of observations. (1) Molecules preventing the VEGF-Flt1 interaction on the precursor membrane (eg, soluble Flt1 receptors) significantly inhibit Mk polyploidization. (2) Addition of exogenous VEGF or placenta growth factor (PlGF) markedly potentiates Mk maturation. Conversely, VEGF does not modify Mo differentiation/maturation. Altogether, our results suggest that in the hematopoietic microenvironment an autocrine VEGF loop contributes to optimal Mk maturation through Flt1. A paracrine loop involving VEGF release by E precursors may also operate. Similarly, recent studies indicate that an autocrine loop involving VEGF and Flt1/Flk1 receptors mediates hematopoietic stem cell survival and differentiation.

Antibodies, Monoclonal↗
PubMed1994

Costimulation of cutaneous T-cell lymphoma cells by interleukin-7 and interleukin-2: potential autocrine or paracrine effectors in the Sézary syndrome.

PURPOSE: To examine interleukin-7 (IL7)- and interleukin-2 (IL2)-induced proliferation of Sézary lymphoma cells and to consider if an autocrine or paracrine growth-stimulatory circuit involving IL7 exists in the Sézary syndrome (SS). MATERIALS AND METHODS: Fresh Sézary lymphoma cells were maintained in short-term culture in the presence of cytokines, and growth was measured by incorporation of (3H)-thymidine (TdR). Expression of IL7 and IL7 and IL2 receptors (IL7-R and IL2-R, respectively) was assessed by polymerase chain amplification of first-strand complementary DNA (RT-PCR), by affinity cross-linking of radioactive iodine-125-IL7, and by dual-color fluorescence-activated cell analysis. IL-7 production was measured by immunoassay. RESULTS: Sézary lymphoma cells from seven patients showed synergistic (five of seven) or additive (two of seven) proliferation when cultured in the presence of IL2 and IL7, as compared with culture with either cytokine alone. Two patients with evidence of synergistic stimulation of [3H]-TdR incorporation showed IL7-R gene expression by RT-PCR and IL7 affinity cross-linking. Incubation of all seven patients' cells with IL7 induced coexpression to varying degrees of IL7-R and IL2-R. Sézary lymphoma cells from at least three of five patients studied expressed IL7 mRNA, and skin from three of five patients studied, as well as normal skin, expressed IL7 mRNA by RT-PCR. CONCLUSION: Sézary lymphoma cells respond by proliferation to IL7 plus IL2, and in some instances produce IL7. Therapeutic maneuvers should be pursued to take advantage of this potential autocrine or paracrine growth-stimulatory mechanism.

Cell Division↗
PubMed1986

Autocrine growth stimulation of the MCF 7 breast cancer cells by the estrogen-regulated 52 K protein.

The growth of MCF 7 human breast cancer cells is stimulated in vitro by estradiol (E2) and we have previously shown that estrogen-regulated glycoproteins released into the culture medium can partly mimic this effect. In this paper, we evaluate the mitogenic activity of the 52 K glycoprotein, which is a major E2-stimulated protein released by MCF 7 cells. The 52 K protein was purified 600-fold by affinity chromatography on Concanavalin A and an anti-52 K monoclonal antibody Sepharose columns. The 99% purified 52 K protein fraction stimulated the growth of estrogen-deprived MCF 7 cells. A mean 1.7-fold increase was obtained with nanomolar concentrations of seven different preparations of 52 K protein. This stimulation represented 40% of the mitogenic effect of E2. Both the 52 K protein and E2 induced microvilli at the cell surface but the effect of the 52 K protein occurred earlier. Other putative growth factors which are also stimulated by E2 and observed by [35S]cysteine labeling did not comigrate with the purified 52 K protein. Finally, the labeled 52 K protein was found to enter MCF 7 cells and to be processed into an immunoreactive 34 K protein. These data indicate that the E2-regulated 52 K glycoprotein is an autocrine mitogen on MCF 7 cells in culture and support the hypothesis that estrogens stimulate the growth of mammary cancer via this (and possibly other) secreted protein(s) acting as autocrine (and paracrine?) growth factors.

Antibodies, Monoclonal↗
PubMed1986

Polyamines and autocrine control of tumor growth by prolactin in experimental breast cancer in culture.

We have previously observed that both polyamines and an autocrine mechanism are involved in the stimulation by ovine PRL (oPRL) of growth of the N-nitrosomethylurea-induced rat mammary tumor cultured in vitro in the soft agar clonogenic assay. These experiments were designed to test the interaction between these two pathways of oPRL action in this system. In agreement with previous findings in our laboratory, conditioned medium obtained from oPRL-treated (oPRL-CM), but not untreated, tumors consistently stimulated colony formation when added to N-nitrosomethylurea mammary tumors plated in soft agar under serum-free medium conditions. Administration of alpha-difluoromethyl-ornithine (DFMO), an irreversible inhibitor of polyamine biosynthesis, abolished the colony-stimulating effect of oPRL-CM. The inhibitory effect of DFMO was reversed in a dose-dependent fashion by the addition of spermidine, which entirely restored the growth-promoting action of oPRL-CM. In addition, the administration of increasing amounts of spermidine potentiated the colony-stimulating effect of suboptimal concentrations of oPRL-CM. In contrast, manipulation of the polyamine environment with DFMO and/or spermidine administration did not affect the number of colonies formed when conditioned medium from untreated tumors was added instead of oPRL-CM. We conclude that the polyamine pathways plays an essential role in the expression of autocrine control of tumor growth by oPRL.

Animals↗
PubMed1988

Autocrine control of prolactin secretion by vasoactive intestinal peptide.

The functions of vasoactive intestinal polypeptide (VIP) and the many other neuropeptides that are localized in the anterior pituitary gland remain unknown although VIP of hypothalamic origin is established to act as a PRL-releasing factor. Evidence is presented here that locally-produced VIP acts in an autocrine fashion to stimulate PRL release. VIP antibodies or a VIP antagonist profoundly but reversibly suppressed PRL secretion in primary cultures of rat pituitary cells or the GH3 cell line. This evidence was obtained with the use of a reverse hemolytic plaque assay for microscopic demonstration of PRL release from individual cells under conditions precluding cell-cell interaction. We suggest that most of the high rate of "spontaneous" PRL secretion attributed to lactotropes deprived of hypothalamic influence is due in fact to the stimulatory effects of VIP acting in an autocrine fashion.

Animals↗
PubMed1991

A proposed role for chromogranin A as a glucocorticoid-responsive autocrine inhibitor of proopiomelanocortin secretion.

Chromogranin A (CgA) is a 50 kilodalton (kDa) acidic glycoprotein that is costored and cosecreted from secretory granules with endogenous hormone from diverse endocrine cell types. The physiological role(s) of CgA is yet to be defined. In this study we used the AtT-20 mouse corticotropic cell line, which produces both CgA and POMC-derived peptides, to study 1) the regulation of CgA and POMC synthesis and secretion, and 2) the influence of CgA on POMC secretion. To study regulation of CgA and POMC biosynthesis and secretion, cells were treated with dexamethasone (DEX) or CRF for 48 h and CgA and POMC messenger RNAs and proteins were analyzed. Exposure to DEX for 48 h (10 nM) inhibited secretion of the 16 K fragment of POMC by 60% while stimulating CgA secretion 500% of control value. Consonant with these changes in protein, POMC mRNA levels fell to 40% of control levels while CgA mRNA levels increased to 250% of control values with DEX treatment. DEX treatment had no effect on the sizes of the CgA [2.1 kilobase (kb)] and POMC (1.0 kb) mRNAs. CRF (100 nM) stimulated secretion of both CgA (4-fold) and ACTH (2.5-fold) above basal values. By contrast, CRF increased POMC mRNA levels but had no effect on levels of CgA mRNA. Changes in total peptide production paralleled the changes in mRNA levels. Because DEX differentially regulated CgA and POMC synthesis and secretion, we questioned whether CgA could function as an autocrine inhibitor of hormone secretion. CgA inhibited CRF-stimulated secretion of 16 K fragment in a concentration-dependent manner (100% at 100 nM) without affecting basal 16 K fragment secretion. Moreover, anti-CgA antiserum, but not nonimmune serum, increased basal 16 K fragment secretion 2-fold and CRF-stimulated 16 K fragment secretion 1.5-fold. These results suggest that CgA plays an autocrine role as a glucocorticoid responsive inhibitor of POMC-derived peptide secretion.

Animals↗